A characteristic of cancer is an abnormal cell proliferation with a broken control mechanism. Most cancer cells grow more rapidly than cells of normal tissues. In the cell division cycle, chromosome duplication is essential and replication of DNA in S phase is tightly regulated. Inhibition of DNA replication has been confirmed to be an effective therapy for cancer treatment and, for example, DNA replication inhibitors such as hydroxyurea (HU), gemcitabine and active metabolites of 5-fluorouracil, and the like are widely used as therapeutic agents for cancer in clinical practice.
Cdc7 is an evolutionally well-conserved serine/threonine kinase and plays an important role in the initiation of DNA replication (non-patent document 1). The kinase activity of Cdc7 is controlled by binding with its activating partner thereof. From the late stage of G1 phase to S phase, Cdc7 forms a complex with Dbf4 (also known as ASK) and phosphorylates Cdc7 substrate to control transition from the G1 phase to the S phase (non-patent document 2). Furthermore, recent studies have reported that Cdc7 plays important roles in both DNA replication and DNA damage signaling pathways (non-patent document 3).
In recent years, Cdc7 kinase is getting a lot of attentions as an attractive target in cancer treatments. Overexpression of Cdc7 is observed in clinical tumors such as breast cancer, colorectal cancer, lung cancer and the like, and many cancer cell lines (non-patent document 4). In some cancer cell lines, an increase in chromosomal copy number of an activating factor, Dbf4, is found. Interestingly, a cancer cell line and an untranformed fibroblast cell line show different responses to suppression of Cdc7 expression using siRNA. The suppression of Cdc7 expression using siRNA causes the S phase arrest in cancer cell lines and induces apoptosis, whereas in normal cells it induces the G1 phase arrest in a p53 activity-dependent manner (non-patent document 5). Furthermore, Cdc7 kinase is activated in the cells under replication stress, and apoptosis induced by hydroxyurea and etoposide increases in the Cdc7 down-regulated cells (non-patent document 6). Thus, a Cdc7 inhibitor, as a single agent or in combination with other chemotherapeutic agents, is useful for a selective cancer treatment.
Patent document 1 describes, as a compound having a Pim kinase inhibitory activity, a compound represented by the formula
wherein A1 and A2 are each independently a hydrogen atom, R1, R2, R3, R4 or hydroxy and the like; A3 is a hydrogen atom, R12, R13, R14 or R15 and the like; R1 is phenyl and the like; R2 is heteroarene and the like; R3 is cycloalkyl and the like; R4 and R15 are alkyl and the like; R12 is phenyl and the like; R13 is heteroarene and the like; R14 is cycloalkyl and the like; and R15 is alkyl and the like.
Patent document 2 describes, as a compound useful for the treatment of diseases relating to Src family tyrosine kinase, a compound represented by the formula
wherein R1 is a hydrogen atom or alkyl and the like; R2 is a hydrogen atom or alkyl and the like; and R3 is a hydrogen atom, alkyl, a hydrogen bond donor or hydrazone crosslinking bound to a hydrogen bond receptor.
Patent document 3 describes, as a protein kinase inhibitor, a compound represented by the formula
wherein X is an oxygen atom or a sulfur atom; Y is an oxygen atom, a sulfur atom or —NR1—; R1 is R, CO2R and the like; R is a hydrogen atom or a C1-6 aliphatic group and the like; R2 is R, N(R)2 and the like; R3 is R or CN and the like; and R4 is R, N(R)2 and the like.
Patent document 4 describes, as a compound having B-Raf kinase inhibitory activity and useful for the treatment of cancer, a compound represented by the formula
wherein R1 is phenyl or a heterocycle and the like; R2 is a hydrogen atom or heteroaryl and the like; R4 is a hydrogen atom or C1-8 alkyl and the like; R5 is a hydrogen atom or a nitro group and the like; R7 is C1-8 alkyl and the like; X is a nitrogen atom and the like; X′ is a sulfur atom or ═C(R3)— and the like, and Z is a sulfur atom or ═C(R3)—, and only one of X′ and Z is ═C(R3)—; and  is a single bond or a double bond, and further describes a compound represented by the formula
wherein each symbol is as defined above.
Patent document 5 describes, as a compound having an IKB kinase β inhibitory activity and useful for the treatment of diseases such as cancer and the like, a compound represented by the formula
wherein X is a sulfur atom and the like; R1 is a hydrogen atom or C1-10 alkyl and the like; R2 is a hydrogen atom or C5-20 heteroaryl and the like; R3 is a hydrogen atom or C1-10 alkyl and the like; R4 and R6 are each a hydrogen atom or C1-5 alkyl and the like; R6 is a hydrogen atom or C1-5 alkyl and the like; and  is a single bond or a double bond, and further describes a compound represented by the formula
wherein each symbol is as defined above.
Patent document 6 describes, as a compound having an inhibitory activity on Tie2 receptor tyrosine kinase, and valuable for the treatment of disease states such as cancer and the like, a compound represented by the formula
wherein A forms, together with the carbon atom bonded thereto, a fused 5-membered heteroaryl ring, wherein the aforementioned heteroaryl ring contains 1 or 2 hetero atoms selected from O, N and S; a 5-membered ring containing G is bonded to the ring formed by A at a meta-position relative to the bridgehead carbon marked with # in the formula; G is selected from O, S and NR5; Z is N and the like; Q1 is aryl, heteroaryl and the like; R1 is a hydrogen atom or a halogen atom and the like; R2 is a hydrogen atom or amino- and the like; R3 is as independently defined for R4 and R6, provided when R3 is not hydrogen and bonded to a nitrogen atom for A, R3 is not halogeno; R5 is as independently defined for R4 and R6, provided R5 is not halogeno; and R4 and R6 are the same or different and each is hydrogen, halogeno, trifluoromethyl, trifluoromethoxy, cyano and the like.
Patent document 7 describes, as a compound effective for the treatment of cell proliferative disorders at least partly mediated by CDC7, PKA and/or Akt, a compound represented by the formula
wherein ring A is nitrogen-containing heteroaryl containing 5 or 6 ring atoms, and 1-4 ring atoms are nitrogen atoms; n is an integer selected from 0 or 1; m is an integer equal to 0, 1 or 2; R is a hydrogen atom, hydroxy and the like; R1 is halo or cyano and the like; R2 and R4 are each independently hydrogen, cycloalkyl and the like; R3 is a hydrogen atom or C1-C5 alkyl and the like; Q is —C(X′)NR6— and the like, wherein X′ is selected from the group consisting of oxygen and sulfur, R6 is hydrogen, C1-C3 alkyl, C1-C3 substituted alkyl and the like, or R6 forms, together with Q, a carbon atom to which Q is bonded, R4 or a carbon atom to which R4 is bonded, heterocyclyl or substituted heterocyclyl and the like.
Patent document 8 describes, as a compound effective for the prophylaxis and/or treatment of inflammatory diseases, a compound represented by the formula
wherein A1 is a nitrogen-containing heteroaryl group optionally having substituent(s); A2 is an aryl group optionally having substituent(s) or a cycloalkyl group optionally having substituent(s); R1 and R2 are each independently a lower alkyl group optionally having substituent(s), an acyl group optionally having substituent(s), an acyloxy group optionally having substituent(s) and the like; m and n are each an integer of 0-2; Q1, Q2, Q3 and Q4 are each selected from C, CH, CH2, C═O, O, N and NH, and one or two of Q1 to Q4 is/are N or NH; and  is a double bond or a single bond.
Patent document 9 describes, as a medicament having a cGMP specific phosphodiesterase inhibitory action and the like, a compound represented by the formula
wherein R1 is a hydrogen atom or a C1-6 alkyl group; R2 is an optionally substituted C3-8 cycloalkyl group, an optionally substituted phenyl group and the like; R3 is a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, O or S and the like; R4 is a hydrogen atom, a C1-6 alkyl group, a hydroxy group, a C1-6 alkoxy group, halogen, a C1-6 haloalkyl group, a nitro group or a cyano group; and R5 is a cyano group, an optionally substituted phenyl group, a saturated or unsaturated heterocyclic group containing 1 to 4 optionally substituted N, O or S and the like.